Many physiologically active agents are best applied topically to obtain desirable results. Topical application, in the form of creams, lotions, gels, solutions, etc., largely avoids side effects of the agents and permits high level concentrations of the agents.
Some therapeutic drugs may also be administered for systemic use through the skin or other body membranes including intransal and intravaginal application of humans and other animals, utilizing a transdermal device or formulated in a suppository or aerosol spray. For some years, pharmaceutical researchers have sought an effective means of introducing drugs into the bloodstream by applying them to the unbroken skin. Among other advantages, such administration can provide a comfortable, convenient and safe way of giving many drugs now taken orally or infused into veins or injected intramuscularly.
Using skin as the portal for drug entry offers unique potential, because transdermal delivery permits close control over drug absorption. For example, it avoids factors that can cause unpredictable absorption from gastrointestinal tract, including changes in acidity, motility, and food content. It also avoids initial metabolism of the drug by the liver known as the first pass effect. Thus, controlled drug entry through skin can achieve a high degree of of control over blood concentrations of drug. Close control over drug concentration in blood can translate readily into safer and more comfortable treatment. When a drug's adverse effects occur at higher concentrations than its beneficial ones, rate control can maintain the concentration that evoke only-or principally the drug's desired actions. This ability to lessen undesired drug actions can greatly reduce the toxicity hazards that now restrict or prevent the use of many valuable agents.
Transdermal delivery particularly benefits patients with chronic disease. Many such patients have difficulty following regimens requiring several doses daily of medications that repeatedly cause unpleasant symptoms. They find the same drugs much more acceptable when administered in transdermal system that require application infrequently-in some cases, only once or twice weekly-and reduce adverse effects.
Transdermal delivery is feasible for drugs effective in amounts that can pass through the skin area and that are substantially free of localized irritating or allergic effects. While these limitations may exclude some agents, many others remain eligible for transdermal delivery. Moreover, their numbers will expand as pharmaceutical agents of greater potency are developed. Particularly suitable for transdermal delivery are potent drugs with only a narrow spread between their toxic and safe blood concentrations, those having gastrointestinal absorption problems, those susceptible to a higher first pass liver metabolism or those requiring frequent dosing in oral or injectable form.
Transdermal therapy permits much wider use of natural substances such as hormones. Often the survival times of these substances in the body are so short that they would have to be taken many times daily in ordinary dosage forms. Continuous transdermal delivery provides a practical way of giving them, and one that can mimic the body's own patterns of secretion.
At present, controlled transdermal therapy appears feasible for many drugs used for a wide variety of ailments including, but not limited to, circulatory problems, hormone deficiency, respiratory ailments, and pain relief.
Percutaneous administration can have the advantage of permitting continuous administration of drug to the circulation over prolonged periods of time to obtain a uniform delivery rate and blood level of drug. Commencement and termination of drug therapy are initiated by the application and removal of the dosing devices from the skin. Uncertainties of administration through the gastrointestinal tract and the inconvenience of administration by injection are eliminated. Since a high concentration of drug never enters the body, problems of pulse entry are overcome and metabolic half-life is not a factor of controlling importance.
The greatest problems in applying physiologically active agents topically or transdermally is that the skin is an effective barrier to penetration. The epidermis of the skin has an exterior layer of dead cells called the stratum corneum which is tightly compacted and oily and which provides an effective barrier against gaseous, solid or liquid chemical agents, whether used alone or in water or in oil solutions. If a physiologically active agent penetrates the stratum corneum, it can readily pass through the basal layer of the epidermis and into the dermis.
Although the effectiveness of the stratum corneum as a barrier provides great protection, it also frustrates efforts to apply beneficial agents directly to local areas of the body. The inability of physiologically active agents to penetrate the stratum corneum prevents their effective use of treating such conditions as inflammation, acne, psoriasis, herpes labialis, herpes genitalis, eczema, infections caused by fungi, viruses and other microorganisms, or other disorders or conditions of the skin or mucous membranes or of conditions beneath the exterior surface of the skin or mucous membranes. The stratum corneum also prevents the skin from absorbing and retaining cosmetic-type materials such as sunscreens, perfumes, mosquito repellents and the like.
Physiologically active agents may be applied to the locally affected parts of the body in the form of a solution, cream, lotion or gel utilizing the vehicle system described herein. These agents may also be delivered for systemic use utilizing the vehicle system in a transdermal patch. Vehicles such as USP cold cream, ethanol and various ointments, oils, solvents and emulsions have been used heretofore to apply physiologically active ingredients locally. Most such vehicles are not effective to carry significant amounts of physiologically active agents into and through the skin. One such vehicle is dimethyl sulfoxide, which is described in U.S. Pat. No. 3,551,554.
My previous inventions disclosed in U.S. Pat. Nos. 3,989,816; 3,991,203; 4,122,170; 4,316,893; 4,415,563; 4,423,040; 4,424,210; 4,444,762 describe a method for enhancing the topical administration of physiologically active agents by combining such an agent with an effective amount of a penetration enhancer and applying the combination topically to humans or animals, in the form of solution, cream, gel, lotion etc. This prior art discloses N-alkyl substituted cyclic lactams as penetration enhancers.
My related U.S. Pat. No. 4,405,616 describes a method for administering systemically active agents through the skin or other body membranes of humans and animals, utilizing a transdermal device or formulation containing an effective amount of a suitable membrane penetration enhancer selected from the disclosed N-alkyl substituted cyclic lactams.
My related U.S. Pat. Nos. 4,461,638 and 4,762,549 describe a method for enhancing delivery of plant nutrients and plant growth regulators, and my U.S. Pat. No. 4,525,199 describes an improved method of pest control by enhancing pesticide permeation.
My related U.S. application, Ser. No. 783,621, now U.S. Pat. No. 4,837,026, filed on Sept. 30, 1985, describes a method for enhancing topical and transdermal administration of physiologically active agents with membrane penetration enhancers selected from the alkanoic acid cyclic amides disclosed therein.
My related U.S. application, Ser. No. 002,387, filed on Jan. 12, 1987, describes a method for enhancing topical and transdermal administration of physiologically active agents with membrane penetration enhancers selected from heterocyclic compounds containing two heteroatoms.
My related U.S. application, Ser. No. 218,316, filed on Jul. 12, 1988, describes a method for enhancing topical and transdermal administration of physiologically active agents with membrane penetration enhancers selected from oxazolidone and related heterocyclic compounds.
My related U.S. application Ser. No. 07/345,457, filed on May 1, 1989, describes a method for enhancing topical and transdermal administration of physiologically active agents with membrane penetration enhancers selected from substituted imidazolines.
My related U.S. application Ser. No. 07/348,387, filed on May 8, 1989 describes a method for enhancing topical and transdermal administration of physiologically active agents with yet another series of membrane penetration enhancers.
Penetration enhancers for enhancing systemic administration of therapeutic agents transdermally disclosed in the art include dodecyl pyrrolidone, dimethyl lauramide and dimethyl sulfoxide. These agents may be used prior to or concurrently with administration of the active agent, see, e.g., U.S. Pat. Nos. 4,031,894; 3,996,934 and 3,921,636.